Early identification of juvenile idiopathic arthritis

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Early identification of juvenile idiopathic arthritis:

A better understanding helps physicians formulate treatment decisions

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The Journal of Musculoskeletal Medicine. Vol. 27 No. 2

By CARA HOFFART, DO DAVID D. SHERRY, MD

Dr Hoffart is a fellow in pediatric rheumatology and Dr Sherry is attending

rheumatologist and director of clinical rheumatology at the Children's

Hospital of Philadelphia.

ABSTRACT: Juvenile idiopathic arthritis (JIA) is a significant cause of

short- and long-term disability, but early disease identification and

treatment lead to improved quality of life. The cause remains unknown. The

diagnosis is made using a detailed history and physical examination with

laboratory and radiographic testing. Common features are morning stiffness

and gelling after inactivity. Any joint may be affected, but large joints

are involved more frequently. Classification of JIA includes 7 subtypes. A

diagnosis is made after other causes of arthritis have been excluded. There

are no laboratory tests to confirm the diagnosis. Synovial fluid analysis

and culture should be performed in children with acute joint swelling and

pain accompanied by fever. Radiography typically is best for the initial

evaluation of arthritis. (J Musculoskel Med. 2010;27:52-56)

Chronic arthritis, a complex condition, is the leading cause of autoimmune

disease in children, affecting about 1 in 1000 worldwide.1 Juvenile

idiopathic arthritis (JIA) collectively describes the group of arthritides

of unknown causes that last more than 6 weeks in children younger than 16

years. Consisting of several subtypes, JIA is a significant cause of short-

and long-term disability.

The goal of JIA management is to achieve remission. However, with less than

full understanding of the disease pathogenesis and a lack of controlled

trials, clinicians are left with little evidence to formulate decisions

about effective treatment.2 Without appropriate treatment, JIA may result in

permanent disability from joint destruction, growth retardation, or

blindness from chronic anterior uveitis.1

However, early disease identification and treatment lead to improved quality

of life for children with JIA. Recent studies showed that as many as 50% of

children who have JIA enter adulthood with active disease,3 and evidence of

ongoing disease into adulthood has led to a shift in the treatment paradigm.

In this 2-part article, we discuss early diagnosis and management of JIA.

This first part reviews the epidemiology, pathogenesis, clinical

manifestations, classification, differential diagnosis, and laboratory

analysis of JIA. In the second part, to appear in a later issue of this

journal, we will explore the treatment options.

EPIDEMIOLOGY

The reported incidence of JIA varies from 1 to 22 cases per 100,000

children, with a prevalence of 8 to 150 cases per 100,000.4,5 Chronic

arthritis in children is defined arbitrarily as arthritis onset earlier than

age 16 years. Onset before age 6 months is very unusual. The highest

frequency occurs between 1 and 3 years, although age varies with subtype.

Twice as many girls as boys are affected with chronic arthritis, but more

boys present with spondyloarthropathy.4

CAUSES/PATHOGENESIS

The cause of JIA remains unknown, but it seems to result from a complex

genetic trait with an immunoinflammatory pathogenesis, possibly influenced

by external antigens.4,5 Abnormalities both cell-mediated (via inflammatory

cells, cytokines, and activated T cells) and humoral (via autoantibodies)

are implicated. The various phenotypes of the disease point toward

interactions of multiple genes affecting immunity and inflammation.

There are HLA associations for each JIA subtype, the strongest in children

with oligoarticular disease. HLA-B27 may contribute to the disease

pathogenesis via molecular mimicry among patients with enthesitis-related

arthritis (ERA).

Immune dysfunction in JIA is evident with the presence of autoantibodies,

such as antinuclear antibodies (ANAs)-present in 40% of patients-and

rheumatoid factor (RF)-present in 5% to 10% of patients.4,5Although

undoubtedly there are genetic predispositions to JIA, other contributing

factors have been suggested, such as environmental agents, infectious

vectors, trauma, psychological stress, and hormonal abnormalities.4,5

CLINICAL MANIFESTATIONS

The diagnosis is made using a detailed history and physical examination in

concordance with appropriate laboratory and radiographic testing. Common

features are morning stiffness and gelling after inactivity. Improvement

frequently occurs as the day progresses. Most young children do not complain

of stiffness or pain, but there may be changes in gait or function.2

Any joint may be affected, but large joints are involved more frequently. An

arthritic joint exhibits inflammation, with swelling, heat, pain, and

decreased range of motion. Although the joints often are warm, they are not

erythematous.4,6

Erythema and extreme pain may be experienced in septic arthritis and in the

reactive arthritides. Attention should be paid to less obvious joints, such

as the temporomandibular joint, because it is involved frequently and may

include significant micrognathia and difficulty in chewing.4

Other joints that may be affected in JIA include the cervical, thoracic, and

lumbosacral spine; hips; and shoulders. Synovitis in these joints cannot be

visualized, but there is limited range of motion or guarding on examination.

The sternoclavicular, acromioclavicular, and sternomanubrial joints rarely

are affected.2,4

In addition to musculoskeletal symptoms, patients may present with anorexia,

weight loss, and growth failure. Significant fatigue is more common in

patients who have systemic disease or polyarticular JIA. The examiner should

evaluate closely for abnormal pupils, rash, lymphadenopathy, hepatomegaly,

splenomegaly, and pericardial or pleural rubs.

Uveitis

Chronic anterior, nongranulomatous uveitis (iridocyclitis) occurs in about

20% of patients with oligoarticular JIA and 10% of patients with

polyarticular JIA (Figure 1).5 Uveitis is most common in girls who have

ANA-positive oligoarticular JIA. Patients usually are asymptomatic, but they

may exhibit conjunctivitis, pupil asymmetry, and eye pain. Patients who have

JIA should be screened routinely. Complications of uveitis include

synechiae, keratotic bands, cataracts, and vision impairment.7

CLASSIFICATION

The International League of Associations for Rheumatology classification of

JIA includes 7 subtypes: oligoarticular JIA, polyarticular RF-positive and

RF-negative JIA, systemic JIA, psoriatic JIA, ERA, and undifferentiated

arthritis.8 Oligoarticular JIA occurs most frequently (50% to 60% of cases),

followed by polyarticular JIA (30% to 35%), systemic JIA (10% to 20%),

psoriatic JIA (2% to 15%), and ERA (1% to 7%).4

Oligoarticular JIA

This subtype is defined as arthritis that affects 4 or fewer joints during

the first 6 months of disease. Patients often are young girls, aged 1 to 4

years, with large joint involvement of the lower extremities, such as the

knees or ankles; one-half present with arthritis in a single knee. About

one-fourth have no pain, and most have little difficulty in functioning.

About 70% are ANA-positive, and none are RF-positive. This patient group,

especially young girls who have a positive ANA, are at greater risk for

asymptomatic uveitis.

Arthritis that remains confined to 4 or fewer joints is classified as

persistent oligoarticular JIA. Patients who recruit 5 or more joints after

the first 6 months are considered to have extended oligoarticular JIA.

Extended disease will develop in up to half of patients; they have only a

12% remission rate, compared with a 75% remission rate in patients with

persistent oligoarticular disease.2,4,5

Polyarticular JIA

This subtype is defined as arthritis that affects 5 or more joints within

the first 6 months of disease. It is divided into 2 groups, RF-positive and

RF-negative. Both affect girls more frequently than boys.

Polyarthritis typically develops in RF-seronegative patients early in

childhood, and they have a better prognosis. Seropositive patients typically

are adolescent girls with severe symmetrical erosive disease of the small

and large joints. The HLA associations in these patients are the same as

those in adults with rheumatoid arthritis and probably represent an early

presentation of this disease.5 Chronic uveitis is less common in

polyarticular than in oligoarticular JIA, but patients still require routine

screening.

Systemic JIA

This subtype is characterized by 2 weeks of fever, high quotidian spikes for

at least 3 days, and at least 1 of the following: evanescent and

erythematous rash, lymphadenopathy, hepatosplenomegaly, and serositis (often

pericarditis or pleuritis). Systemic JIA affects boys and girls equally; it

may occur at any time but is most common in the early years of childhood.

Children appear quite ill when febrile but are well-appearing when they

defervesce.

Because arthritis may not occur for several months after the initial

symptoms, a definitive diagnosis may be delayed. The arthritis usually is

polyarticular. Typical laboratory findings include anemia, leukocytosis,

thrombocytosis, elevated liver enzyme levels, and elevated acute phase

reactant levels (the C-reactive protein [CRP] level usually is

disproportionately higher than the erythrocyte sedimentation rate [ESR]).

Results of the ANA titer are rarely positive.

A rapidly improved ESR may not be indicative of disease quiescence. It is

associated with macrophage activation syndrome, a life-threatening

complication of systemic JIA characterized by hemophagocytosis. Patients are

ill, and a severe coagulopathy develops. Sixty percent to 85% of patients

with systemic JIA go into remission, but a chronic destructive polyarthritis

develops in up to 37% of patients.4-6

Enthesitis-related arthritis

ERA occurs most frequently in boys older than 8 years. This subtype includes

juvenile ankylosing spondylitis and arthritis associated with inflammatory

bowel disease (IBD). There is a high frequency of HLA-B27 association and a

positive family history.

Patients with ERA demonstrate pain, stiffness and, eventually, decreased

mobility of the back. Peripheral arthritis typically precedes axial

involvement. The hallmark of this form is enthesitis (inflammation at tendon

insertions). Sacroiliac arthritis develops in many patients; it can be

appreciated on radiographs as joint-space narrowing, erosions, sclerosis,

osteoporosis, and fusion (a late finding).5

Articular manifestations may be the first signs of IBD. Therefore, screening

for GI symptoms, growth failure, erythema nodosum, and aphthous stomatitis

is important.

Acute uveitis develops in about 27% of patients with ERA. However, the

uveitis in ERA is symptomatic, with redness, pain, and photophobia, and

typically is unilateral and recurrent.2,4,6

Psoriatic JIA

This subtype is arthritis that occurs in conjunction with psoriasis or

psoriatic features. It is more common in girls and typically peaks in

mid-childhood. Diagnosis may be difficult because the arthritis may precede

skin findings by years.

Psoriatic JIA is an asymmetrical arthritis that affects the knees, ankles,

and small joints of the hands and feet. Dactylitis, or diffuse swelling of

the fingers and toes-often described as a " sausage digit " -is not uncommon

(Figure 2). Extra-articular manifestations include nail changes, such as

pitting and onycholysis, and asymptomatic uveitis. The RF is negative, but

ANAs may be positive.4,5

Undifferentiated arthritis

This subtype of JIA includes patients who do not meet criteria for any

category. Or, they meet the criteria for more than 1 category but with

either a close relative who has psoriasis or the presence of RF.

DIFFERENTIAL

A diagnosis of JIA is made after other causes of arthritis have been

excluded. Clinical findings (eg, rash, systemic illness, arthritis character

and duration, length of fever, and evidence of a previous infection) help

differentiate JIA from other underlying causes of symptoms.

The differential diagnosis of arthritis may be subdivided into general

categories of reactive arthritis (usually postenteric infection but may be

post-sexually transmitted disease), inflammatory or autoimmune disease

(lupus, dermatomyositis, IBD, cystic fibrosis), infection (especially Lyme),

systemic illness (sarcoidosis), neoplasia (pigmented villonodular synovitis,

leukemia, lymphoma), and trauma (occult fracture, foreign body) (Table).

Often, a distinction may be made between oligoarticular JIA and other causes

on the basis of history of antecedent infection and arthritis less than 6

weeks duration. Septic arthritis is considered in a patient with acute onset

of fever, joint swelling, and erythema in addition to exquisite joint pain.

Synovial fluid should be obtained and cultured and antibiotics should be

started immediately because septic arthritis may lead quickly to joint

destruction. Patients with gonococcal arthritis may have fever, chills, and

rash in addition to arthritis. A complete sexual history is pertinent.5

A misdiagnosis of JIA may be made when children present with arthralgia and

bone pain. Bone tenderness should raise suspicion for underlying malignancy.

There often is a discrepancy in laboratory testing in these patients. They

may have thrombocytopenia relative to an elevated ESR. If there is an

elevated ESR, thrombocytosis would be expected because both are acute phase

reactants.

Multisystem rheumatologic disease may be distinguished from JIA by clinical

features and laboratory findings. Systemic lupus erythematosus (SLE) often

presents in adolescence with fever, rash, and nonerosive arthritis. The ANA

is positive in SLE but also may be present in oligoarticular and

polyarticular JIA. Both SLE and systemic-onset JIA may manifest as fever and

serositis, but the skin findings are different. In addition, malar rash,

nephritis, cytopenia, hypocomplementemia, and anti-double-stranded DNA and

other autoantibodies are seen only in SLE. Patients with dermatomyositis may

have polyarthritis early, but development of pathognomonic skin findings and

muscle weakness rule out JIA.1,5

Orthopedic complaints associated with patellofemoral syndrome and

Osgood-Schlatter disease are common in active adolescents who complain of

knee pain. They typically do not awaken with morning stiffness, and their

pain worsens with exercise. Musculoskeletal pain without arthritis is seen

in chronic pain syndromes, such as reflex neurovascular dystrophy. Features

include allodynia (pain to light touch) and pain out of proportion to

examination findings.

LABORATORY ANALYSIS

Although directed laboratory tests may support the diagnosis of JIA or

provide evidence of inflammation, there are no laboratory tests to confirm

the diagnosis. Initial laboratory evaluation for a child with suspected

arthritis should include a complete blood cell count with differential, CRP

level, and ESR. In addition to documenting the presence or absence of

systemic inflammation, these tests can identify hematological abnormalities

that may reflect malignancy. Serological testing for Lyme disease is

recommended in children who have oligoarthritis and live in areas in which

Lyme disease is endemic. Among children with clinically confirmed JIA, an

ANA test can help determine the risk of uveitis. The ANA result may be

positive in up to 20% of normal children; thus, an elevated ANA level is not

diagnostic of JIA, and care should be taken in interpreting a positive

result in someone who does not have arthritis.

RF positivity is infrequent in JIA and unusual in children younger than 7

years; therefore, it is not a good screening test for diagnosis. RF

positivity is more common in children who have disease onset at a later age,

polyarticular disease, or subcutaneous rheumatoid nodules. Seropositivity is

associated with erosive synovitis and poorer prognosis. HLA-B27 is not

diagnostic but is associated with reactive arthritis, IBD, and ERA.4,6

Analysis of synovial fluid

Synovial fluid analysis and culture should be performed in children with

acute joint swelling and pain accompanied by fever or for whom the diagnosis

is uncertain or an infectious cause is suspected. Gout and pseudogout are

extremely rare in children and only under the most unusual circumstances

does synovial fluid need to be sent for crystal analysis. Synovial fluid

should be analyzed at the time of an intra-articular corticosteroid

injection, if possible. In JIA, the synovial fluid usually is yellow and

cloudy, with decreased viscosity.

Leukocyte counts are elevated (typically between 15,000 and 20,000/µL, but

may be higher), with neutrophil predominance. Synovial fluid leukocyte

counts of 2000 to 50,000/µL are defined as inflammatory; with higher counts,

infection needs to be considered.

Imaging

Radiography typically is best for the initial evaluation of arthritis to

look for juxta-articular osteopenia, erosions, growth-arrest lines,

fractures, and other bony abnormalities, but these abnormalities may not be

apparent for several months. Among children with JIA, radiographic features

include, in order of progression, soft tissue swelling, widening or

narrowing of the joint space, osteoporosis, erosions, subluxation, and

ankylosis. Erosive changes are uncommon before 2 years of active disease.

Other useful imaging modalities include ultrasonography, bone scanning, and

MRI. Ultrasonography is a noninvasive and inexpensive method to confirm a

joint effusion. Bone scans help detect osteomyelitis, malignancy, and joints

that have subclinical inflammation. MRI is the most sensitive technique for

identifying soft tissue abnormalities and early erosions. It is especially

useful in looking at joints otherwise difficult to evaluate, such as the

temporomandibular (TMJ), hip, and sacroiliac joints, as well as at TMJ

arthritis.4

For children with JIA, early disease identification and treatment leads to

improved quality of life.